慢性阻塞性肺疾病合并肺曲菌病一例及文献复习

目的:提高对慢性阻塞性肺疾病合并侵袭性肺曲菌病(COPD合并IPA)临床特点、诊断及治疗的认识.方法:回顾性分析2011年4月收治的一例COPD合并IPA患者的临床资料及诊治经过,并复习相关文献.结果:男患,“咳嗽、咳痰30余年,气短3年,加重1月余”入院,肺部CT示双肺多发结节影、空洞影,经抗炎、抗念珠菌治疗无效,CT下肺结节病灶活检病理示肺曲菌.抗曲菌治疗后症状好转、肺部影像明显吸收.结论:COPD合并IPA正逐渐引起重视,临床特征无明显特异性,肺部影像以结节影、空洞影多见,早期常规治疗无效时应积极抗曲菌治疗,可明显改善症状,降低死亡率,病理活检是确诊的依据.     

Systemic dissemination of chronic necrotizing pulmonary aspergillosis in an elderly woman without comorbidity: a case report

ABSTRACT: INTRODUCTION: Chronic necrotizing pulmonary aspergillosis usually occurs in mildly immune-compromised hosts or those with underlying pulmonary disease. The radiographic pattern of chronic necrotizing pulmonary aspergillosis is typically a progressive upper lobe cavitary infiltrate with pleural thickening. We report here an atypical case of chronic necrotizing pulmonary aspergillosis mimicking lung cancer, which developed into a disseminated fatal disease in an older woman with no comorbidity. CASE PRESENTATION: An 80-year-old Japanese woman was referred to our hospital for a chest roentgenogram abnormality. Repeated fiber-optic bronchoscopy could not confirm any definite diagnosis, and she refused further examinations. Considering the roentgenogram findings and her age, she was followed-up as a suspected case of lung cancer without any treatment. Then, 10 months later, she complained of visual disturbance and was admitted to our department of ophthalmology. She was diagnosed as having endophthalmitis. After treatment with corticosteroids for 20 days, she developed acute encephalitis and died four weeks later. Autopsy revealed dissemination of Aspergillus hyphae throughout her body, including her brain. CONCLUSIONS: In older patients, even if they do not have any comorbidity, chronic necrotizing pulmonary aspergillosis should be added to the differential diagnosis of solitary pulmonary lesions in a chest roentgenogram.     

Recombinant human macrophage colony-stimulating factor augments pulmonary host defences against Aspergillus fumigatus

The in vivo and ex vivo effects of macrophage colony-stimulating factor (M-CSF) were studied in a profoundly neutropenic rabbit model in order to determine its potential to augment pulmonary host defence against Aspergillus. M-CSF (100-600 microg/kg/d) was administered prophylactically to neutropenic rabbits with pulmonary aspergillosis starting three days pre-inoculation and then throughout neutropenia. Rabbits receiving M-CSF had significantly increased survival (P=0.01) and decreased pulmonary injury, as measured by decreased pulmonary infarction (P=0.004), when compared with untreated controls. Microscopic studies demonstrated greater numbers of activated pulmonary alveolar macrophages (PAMs) in lung tissue of rabbits receiving M-CSF, in comparison to controls (P<0.001). PAMs harvested from rabbits treated with M-CSF had a significantly greater percent phagocytosis of Aspergillus fumigatus conidia than did PAMs from controls (P=0.04). These data indicate that prophylactic administration of M-CSF augments pulmonary host defence against A. fumigatus and suggest a potential role for this cytokine as adjunctive therapy in the treatment of pulmonary aspergillosis in the setting of profound neutropenia.     

Invasive pulmonary aspergillosis: retrospective case record review

Invasive pulmonary aspergillosis is a severe infection, with a sharp increase during the last decades. Our study aimed at identification of the epidemiological characteristics of invasive pulmonary aspergillosis during a period of four years. All clinical records with pulmonary isolation of Aspergillus species were reviewed, as a part of surveillance program at Reina Sofia University Hospital, from January 1995 to December 1998. Diagnosis of invasive pulmonary aspergillosis was based on criteria of Centers for Disease Control and Prevention. Of the 50 patients identified 78% were males and 44% were current or ex-smokers. Chronic respiratory diseases were identified in 64% of them, and 60% were receiving immunosuppressives. Twenty percent of our patients had been subjected to lung transplantation and 28% to organ transplantation in general. Only 78% had received specific antifungal treatment and 56% had fatal prognosis. Our findings match with previous studies, apart from the high frequency of lung transplantation in our series. We recommend further studies on large prospective cohorts.     

自身免疫性大疱病合并侵袭性肺曲霉病:3例报告

目的通过典型病例回顾探讨自身免疫性大疱病糖皮质激素治疗过程中合并肺曲霉病的诊断和治疗情况。方法报告3例自身免疫性大疱病合并侵袭性肺曲霉病病例。3例病例均行痰镜检、培养、抗原检测、胸部CT或者坏死组织病理检查。分离病原菌经形态学和分子生物学鉴定为烟曲霉、黄曲霉和刺孢裸胞壳。结果 3例病例证实为侵袭性肺曲霉病。进行以伏立康唑为主的综合治疗后均治愈。结论自身免疫性大疱病糖皮质激素治疗过程中应警惕肺曲霉病的发生。多种实验室检查可以帮助早期诊断,提高疗效。     

非粒细胞减少患者肺曲霉病22例回顾性分析

目的提高对非粒细胞减少患者肺曲霉病的认识及诊疗水平。方法回顾性分析22例非粒细胞减少患者肺曲霉病的临床、影像学及实验室资料,随诊其转归。结果22例肺曲霉病（PA）患者,男性12例,女性10例,平均年龄（56．3±21．4）岁。确诊、临床诊断各8例,拟诊6例。侵袭性肺曲霉病（IPA）11例,单纯性曲霉球6例,慢性坏死性肺曲霉病（CNPA）5例。常见基础疾病为继发型肺结核（8／22）、糖尿病或类固醇性糖尿病（6／22）、高血压病（5／22）、慢性阻塞性肺疾病（5／22）,4例系原发社区感染。常见临床症状咳嗽咳痰（18／22）、咯血（11／22）、气促（7／22）。影像学表现为肺部渗出或实变病灶9例、空洞改变及典型曲霉球12例,结节或肿块1例。首选药物治疗依次为伏立康唑（10／22）、卡泊芬净（4／22）、伊曲康唑（3／22）。结论非粒细胞减少伴IPA好发于糖尿病、慢性阻塞性肺疾病,亦可发生在免疫功能正常患者。单纯曲霉球多继发或并发于肺结核。应注意鉴别CNPA与单纯曲霉球。IPA临床表现缺乏特征性。影像改变未见典型晕征及空气半月征,肺外播散少见,药物治疗首选伏立康唑。     

IL-37 Inhibits Inflammasome Activation and Disease Severity in Murine Aspergillosis

Since IL-37 transgenic mice possesses broad anti-inflammatory properties, we assessed whether recombinant IL-37 affects inflammation in a murine model of invasive pulmonary aspergillosis. Recombinant human IL-37 was injected intraperitoneally into mice prior to infection and the effects on lung inflammation and inflammasome activation were evaluated. IL-37 markedly reduced NLRP3-dependent neutrophil recruitment and steady state mRNA levels of IL-1β production and mitigated lung inflammation and damage in a relevant clinical model, namely aspergillosis in mice with cystic fibrosis. The anti-inflammatory activity of IL-37 requires the IL-1 family decoy receptor TIR-8/SIGIRR. Thus, by preventing activation of the NLRP3 inflammasome and reducing IL-1β secretion, IL-37 functions as a broad spectrum inhibitor of the innate response to infection-mediated inflammation, and could be considered to be therapeutic in reducing the pulmonary damage due to non-resolving Aspergillus infection and disease.     

P67-phox (NCF2) lacking exons 11 and 12 is functionally active and leads to an extremely late diagnosis of chronic granulomatous disease (CGD)

Two brothers in their fifties presented with a medical history of suspected fungal allergy, allergic bronchopulmonary aspergillosis, alveolitis, and invasive aspergillosis and pulmonary fistula, respectively. Eventually, after a delay of 50 years, chronic granulomatous disease (CGD) was diagnosed in the index patient. We found a new splice mutation in the NCF2 (p67-phox) gene, c.1000 + 2T → G, that led to several splice products one of which lacked exons 11 and 12. This deletion was in frame and allowed for remarkable residual NADPH oxidase activity as determined by transduction experiments using a retroviral vector. We conclude that p67-phox which lacks the 34 amino acids encoded by the two exons can still exert considerable functional activity. This activity can partially explain the long-term survival of the patients without adequate diagnosis and treatment, but could not prevent progressing lung damage.     

Invasive pulmonary aspergillosis due to a mixed infection caused by Aspergillus flavus and Aspergillus fumigatus

Invasive pulmonary aspergillosis is typically caused by a single Aspergillus species, most frequently Aspergillus fumigatus. Here we report that a lung transplant recipient developed invasive aspergillosis due to a mixed infection caused by Aspergillus flavus and A. fumigatus. The implications for this unusual finding are discussed.     

A case of chronic necrotizing pulmonary aspergillosis due toAspergillus nidulans

A 55-year old man without immunosuppression clinically showed a coin lesion in the right lower lung on the chest radiographs.Aspergillus nidulans was isolated and identified in both trans-bronchial lung biopsy specimen and resected tissue. The specimens revealed characteristics of chronic necrotizing pulmonary aspergillosis pathologically. Very few reports on cases of pulmonary aspergillosis due toA. nidulans exist, and we were not able to find any reports of similar cases. This case may be the first reported case of chronic necrotizing pulmonary aspergillosis due toA. nidulans.     

Invasive Pulmonary Fungal Infections in Cystic Fibrosis

Invasive pulmonary mycosis is after allergic bronchopulmonary aspergillosis (ABPA) a frequent and severe complication of CF lung disease. Among CF caregivers, there is an insecurity when and how to treat infections of the lung parenchyma caused by different fungi in patients with CF. This case series provides a multicenter experience on diagnostic, manifestation, and treatment of non-ABPA cases of pulmonary. Non-ABPA cases of pulmonary mycoses in patients with CF have been collected from the CF Centers in Berlin, Essen, Worms, Frankfurt (Germany), Leeds (UK), and Barcelona (Spain). Non-ABPA was defined as total serum IgE level <500 kU/L. Scedosporium and Lomentospora species seem to be more virulent in patients with CF and have been successfully treated with triple antifungal drug regimens in several cases. Rare fungi including yeasts can have pathogenic potential in CF. In this series, antibiotic treatment failure was the main indicator for the initiation of antifungal treatment. For an early and effective treatment of pulmonary mycoses in CF, the identification of biomarkers and of risk factors beyond antibiotic treatment failure is crucial and urgently needed. Furthermore, treatment efficacy studies are necessary for the different causative agents of these infections.     

肺曲霉病40例的临床分析

目的：探讨肺曲霉病的临床表现、影像学特点、诊断和治疗,以提高对本病的认识。方法：回顾性分析本院2002年1月-2009年4月经病理确诊为肺曲霉病住院患者40例,总结其临床表现、影像学特点、诊断及治疗情况。结果：40例肺曲霉病患者中,曲菌球23例、侵袭性肺曲霉病17例。合并有基础疾病者36例（90．0％）：其中,肺结核15例（37．5％）,支气管扩张6例（15．0％）。肺曲霉病的主要症状为咳嗽32例（80．0％）,咳痰25例（62．5％）,咯血24例（60．0％0。影像学表现多样,肿块结节型23例（57．5％）,渗出型12例（30．0％）空洞样病灶12例（30．0％）,“洞中球征”和“晕征”各8例（20．0％）。所有病例均经过病理检出,手术切除后病理检出26例（65．0％）,纤维支气管镜下活检栓出12例（30．0％）,CT引导下经皮肺穿刺活检检出2例。本组病例中,26倒在病理诊断前被初诊误诊,误诊率高达65．0％,初诊为肺结核13例（32．5％）,肺癌8例（20．0％）,细菌感染3例,支气管扩张并感染2例。26例（65．0％）经外科手术切除,随访均无复发;10例（25．O％）经抗真菌药物治疗,9例痊愈或显效。结论：肺曲霉病多继发于肺部基础疾病,临床表现以咳嗽、咳痰、反复间断咯血为主,缺乏特异性;影像学表现复杂多样。曲菌球和侵袭性肺曲霉病的发病危险因素、临床表现、影像学以及治疗方法均有不同。肺曲霉病误诊率高,确诊有赖于组织病理学;外科治疗和抗真菌药物治疗有较好的疗效。     

CXC chemokine receptor-2 ligands are necessary components of neutrophil-mediated host defense in invasive pulmonary aspergillosis

Invasive pulmonary aspergillosis is a devastating complication of immunosuppression, which occurs in association with neutrophil dysfunction or deficiency. ELR+ CXC chemokines are a subfamily of chemokines that play a critical role in neutrophil chemotaxis and activation both in vitro and in vivo. We hypothesized that interaction of these ligands with CXC chemokine receptor-2 (CXCR2), their sole murine receptor, is a major component of neutrophil-dependent pulmonary host defense against Aspergillus fumigatus. In immunocompetent animals, neutrophils were recruited to the lung in response to intratracheally administered A. fumigatus conidia. In a model of transient in vivo depletion of neutrophils, animals developed invasive pulmonary aspergillosis, associated with delayed influx of neutrophils into the lung. In both normal and neutrophil-depleted animals, the ELR+ CXC chemokines MIP-2 and KC were induced in response to intratracheal administration of conidia. Ab-mediated neutralization of the common ELR+ CXC chemokine receptor, CXCR2, resulted in development of invasive disease indistinguishable from the disease in neutrophil-depleted animals, while control animals were highly resistant to the development of infection. CXCR2 neutralization was associated with reduced lung neutrophil influx and resulted in a marked increase in mortality compared with controls. In contrast, animals with constitutive lung-specific transgenic expression of KC were resistant to the organism, with reduced mortality and lower lung burden of fungus. We conclude that CXCR2 ligands are essential mediators of host defense against A. fumigatus, and may be important targets in devising future therapeutic strategies in this disease.     

Allergic Aspects of Aspergillosis

Aspergillus species and principally A. fumigatus cause a spectrum of pulmonary diseases depending on underlying host genetic risk factors. These include invasive aspergillosis, hypersensitivity lung disease, allergic asthma, allergic bronchopulmonary aspergillosis, and mycetomas. These disorders, pathogenesis and host risk factors will be discussed.     

Breakthrough pulmonary Aspergillus fumigatus infection with multiple triazole resistance in a Spanish patient with chronic myeloid leukemia

BackgroundAn allogeneic hematopoietic cell transplantation (allo-HCT) patient presented with chronic pulmonary aspergillosis associated to pulmonary graft versus host disease (GVHD) and was treated for a long time with several antifungal agents that were administered as prophylaxis, combination therapies, and maintenance treatment. The patient suffered from a breakthrough invasive pulmonary aspergillosis due to Aspergillus fumigatus after long-term antifungal therapy.Material and methodsSeveral isolates were analyzed. First isolates were susceptible in vitro to all azole agents. However, after prolonged treatment with itraconazole and voriconazole a multiple azole resistant A. fumigatus isolate was cultured from bronchoalveolar lavage (BAL) when the patient was suffering from an invasive infection, and cavitary lesions were observed.ResultsAnalysis of the resistant mechanisms operating in the last strain led us to report the first isolation in Spain of an azole resistant A. fumigatus strain harboring the L98H mutation in combination with the tandem repeat (TR) alteration in CYP51A gene (TR-L98H). Long-term azole therapy may increase the risk of resistance selecting strains exhibiting reduced susceptibility to these compounds. However, since the isolates were genetically different the suggestion that could be made is that the resistance was not induced during the prolonged azole therapy but the patient might simply have acquired this resistant isolate from the environment, selected by the therapy.ConclusionsThese findings suggest that in all long-term treatments with antifungal agents, especially with azoles, repeated sampling and regular susceptibility testing of strains isolated is necessary as resistant isolates could be selected.     

Visualization of Intrapulmonary Lymph Vessels in Healthy and Inflamed Murine Lung Using CD90/Thy-1 as a Marker

Background

Lymphatic vessels play a pivotal role in fluid drainage and egress of immune cells from the lung. However, examining murine lung lymphatics is hampered by the expression of classical lymph endothelial markers on other cell types, which hinders the unambiguous identification of lymphatics. The expression of CD90/Thy-1 on lymph endothelium was recently described and we therefore examined its suitability to identify murine pulmonary lymph vessels under healthy and inflammatory conditions.

Methodology/Principal Findings

Immunohistochemistry with a monoclonal antibody against CD90.2/Thy-1.2 on 200 µm thick precision cut lung slices labeled a vascular network that was distinct from blood vessels. Preembedding immunostaining and electron microscopy verified that the anti-CD90.2/Thy-1.2 antibody labeled lymphatic endothelium. Absence of staining in CD90.1/Thy-1.1 expressing FVB mice indicated that CD90/Thy-1 was expressed on lymph endothelium and labeling was not due to antibody cross reactivity. Double-labeling immunohistochemistry for CD90/Thy-1 and α-smooth muscle actin identified two routes for lymph vessel exit from the murine lung. One started in the parenchyma or around veins and left via venous blood vessels. The other began in the space around airways or in the space between airways and pulmonary arteries and left via the main bronchi. As expected from the pulmonary distribution of lymph vessels, intranasal application of house dust mite led to accumulation of T cells around veins and in the connective tissue between airways and pulmonary arteries. Surprisingly, increased numbers of T cells were also detected around intraacinar arteries that lack lymph vessels. This arterial T cell sheath extended to the pulmonary arteries where lymph vessels were located.

Conclusions/Significance

These results indicate that CD90/Thy-1 is expressed on lymphatic endothelial cells and represents a suitable marker for murine lung lymph vessels. Combining CD90/Thy-1 labeling with precision cut lung slices allows visualizing the anatomy of the lymphatic system in normal and inflamed conditions.     

Animal models of allergic bronchopulmonary aspergillosis

Among the allergic fungi, Aspergillus fumigatus, a saprophytic mold, distributed widely in the environment is a frequently recognized etiologic agent in a number of allergic conditions. Among the different allergic diseases caused by this fungus, allergic bronchopulmonary aspergillosis (ABPA) is by far the most significant one. The immunopathogenesis of this disease is not fully understood. Although several immunomodulatory treatments are available for allergic disease, none of them are applicable or relevant or useful in fungal induced allergy. It is essential to understand the pathogenesis of the disease including the antigen induced immunoregulation and the resulting factors, such as cytokine, chemokines, pathways activating factors, inflammatory and airway remodeling factors need to be understood for intervening with appropriate treatment. Animal models are essential in understanding these features of the disease. Several models of allergic aspergillosis have been developed in recent years in various animals. However, murine models have been studied more carefully and extensively. The exposure to antigen in mice leads to allergy very similar to ABPA with high IgE, elevated peripheral blood and lung eosinophils, pulmonary inflammation, and airway hyperreactivity. The role of various cytokines and chemokines and their receptors were also studied. In addition, immunotherapy and vaccination have been attempted in recent years using the murine model of ABPA. This review covers the murine model of Aspergillus induced allergy and asthma and presented critically our current understanding of the subject and the potential application of such a model in future for developing treatment modalities. This revised version was published online in June 2006 with corrections to the Cover Date.     

An experimental model of pulmonary aspergillosis

The model of experimental chronic pulmonary aspergillosis has been obtained in mice and guinea pigs by the intrapulmonary infection of the animals with the suspension of Aspergillus mycelium and spores in complete Freund's adjuvant. Such method of infection has made it possible to produce chronic local mycotic process. Morphologically, focal inflammatory changes of the lung tissue with the subsequent formation of a multitude of small abscesses in these areas have been observed as characteristic manifestations of aspergillosis.     

Progressive dyspnoea following the treatment of Mycobacterium abscessus infection in an individual with relapsing granulamatosis with polyangitis (Wegener's), complicated by hearing loss requiring cochlear implantation

ABSTRACT: BackgoundGranulomatosis with polyangitis (Wegener's) is a vasculitic disease predominantly affecting the lungs, skin, kidneys, ears, nose and throat. Mycobacterium abscessus is an uncommon rapidly growing mycobacterium causing sporadic lung disease. This is the first report of both GPA and Mycobacterium abscessus pulmonary disease reported in the literature.Case PresentationWe present a case report of a 33 year old Caucasian man with relapsing disease complicated by pulmonary infection with Mycobacterium abscessus. He subsequently required bilateral cochlear implantation for progressive sensori-neural hearing loss. His M. abscessus was treated successfully with a prolonged course of antimicrobial therapy. His Granulomatosis with polyangitis (Wegener's) relapsed towards the end of antimicrobial therapy and required treatment. Shortly after completing his antimicrobial therapy and relapse, he developed progressive dyspnea due to pulmonary fibrosis. CONCLUSION: The potential causes of his progressive dyspnoea are discussed including the potential role of his underlying disease and treatment.     

A case of pulmonary aspergillosis with lack of response to caspofungin

Currently, susceptibility testing of Aspergillus isolates towards caspofungin is hampered by a lack of interpretative cut-off values. Nevertheless, caspofungin has been widely recommended for the treatment of invasive aspergillosis. This antifungal, however, could lead to therapy failure as demonstrated by the case in this report of a 55-year-old patient, who eight months after the diagnosis of leukemia and successful allogenic hematopoietic stem cell transplantation (HSCT), succumbed to a fatal pulmonary aspergillosis infection, which resisted treatment with caspofungin.